[go: up one dir, main page]

WO2018218357A1 - Méthodes de diagnostic et de traitement de la cachexie - Google Patents

Méthodes de diagnostic et de traitement de la cachexie Download PDF

Info

Publication number
WO2018218357A1
WO2018218357A1 PCT/CA2018/050639 CA2018050639W WO2018218357A1 WO 2018218357 A1 WO2018218357 A1 WO 2018218357A1 CA 2018050639 W CA2018050639 W CA 2018050639W WO 2018218357 A1 WO2018218357 A1 WO 2018218357A1
Authority
WO
WIPO (PCT)
Prior art keywords
tnfa
cachexia
acid
carboxyl
aurin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CA2018/050639
Other languages
English (en)
Inventor
Patrick L. Mcgeer
Moonhee Lee
Edith G. Mcgeer
Krista KENNEDY
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aurin Biotech Inc
Original Assignee
Aurin Biotech Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Aurin Biotech Inc filed Critical Aurin Biotech Inc
Priority to EP18810657.9A priority Critical patent/EP3630121A4/fr
Priority to CA3059278A priority patent/CA3059278A1/fr
Priority to JP2019558441A priority patent/JP2020521723A/ja
Priority to US16/605,785 priority patent/US20200121697A1/en
Publication of WO2018218357A1 publication Critical patent/WO2018218357A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/603—Salicylic acid; Derivatives thereof having further aromatic rings, e.g. diflunisal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6863—Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/52—Assays involving cytokines
    • G01N2333/525—Tumor necrosis factor [TNF]

Definitions

  • This invention relates to diagnosing and treating cachexia, including cancer cachexia.
  • Cachexia is a complex pathological syndrome with symptoms including weight loss, muscle atrophy, appetite loss and fatigue.
  • Tumor necrosis factor alpha also termed cachexin, is a cytokine associated with cachexia.
  • Cachexia affects the majority of terminal cancer patients, and increases patient morbidity and mortality.
  • Cachexia is often the immediate cause of death itself in cancer patients.
  • Cachexia is also seen in non-cancer contexts, including in HIV/AIDS, end-stage renal failure, chronic obstructive pulmonary disease (COPD), and geriatric cachexia.
  • TNFa as an endogenously produced factor which could attack cancer cells set off a plethora of studies involving different types of cancers and different paradigms of experimentation. For example, this led to a clinical trial by Selby et al. (1987) of TNFa in advanced cancer cases with disastrous results. These, and other apparently inexplicable results, led to contradictory conclusions as to the properties of TNFa and confusion regarding the reasons for such contradictions. The situation has been
  • aspects of the invention relate to treating cachexia through administration of complement inhibitors to reverse elevated TNFa production associated with cachexia.
  • complement inhibitors dimers of acetyl salicylic acid such as 4,4'-diacetoxy-1 , 1 biphenyl-3,3' dicarboxylic acid (DAS)
  • DAS 4,4'-diacetoxy-1 , 1 biphenyl-3,3' dicarboxylic acid
  • APAC aurin polycarboxylic acid complex
  • Types of cachexia treated include terminal stage cancer, as well as non-cancer conditions such as HIV/AIDS, end-stage renal failure, chronic obstructive pulmonary disease (COPD), and geriatric cachexia.
  • aspects of the invention also relate to diagnosing and monitoring cachexia through determining salivary levels of TNFa.
  • the inventors have determined that TNFa is produced at a low level by all organs of the body, presumably to establish and maintain the capillaries that provide their blood supply.
  • the inventors show that TNFa is secreted in saliva, which is indicative of mandibular gland production, and can act as an indicator of production in brain or other organs.
  • Salivary TNFa production has been determined to be constant in healthy individuals and elevated in patients with cachexia. Types of cachexia that can be diagnosed and monitored include terminal stage cancer, as well as non-cancer conditions such as HIV/AIDS, end-stage renal failure, chronic obstructive pulmonary disease (COPD), and geriatric cachexia.
  • COPD chronic obstructive pulmonary disease
  • An aspect of the invention provides a method of treating cachexia comprising administering to a human in need thereof an effective amount of a complement inhibitor.
  • the complement inhibitor may be a dimer of acetyl salicylic acid or a pharmaceutically acceptable salt thereof.
  • the dimer of acetyl salicylic acid may be 4,4'-diacetoxy-1 ,1 biphenyl-3,3' dicarboxylic acid (DAS), 5,5'-methylenebis(2-hydroxybenzoic acid), or pharmaceutically acceptable salts thereof.
  • the complement inhibitor may also be selected from the group consisting of aurin tricarboxylic acid (5,5'-((3-carboxyl-4-oxocyclohexa-2,5-diene)methylene)bis(2-hydroxybenzoic acid)), aurin quadracarboxylic acid
  • the complement inhibitor may comprise aurin tri-, quadra-, penta- and hexacarboxylic acids, or
  • the complement inhibitor may alternatively be an inhibitor of formation of the membrane attack complex C5b-9.
  • the complement inhibitor may be an ester prodrug of a dimer of acetyl salicylic acid, or aurin tri-, quadra- , penta- or hexacarboxylic acid, or a pharmaceutically acceptable salt thereof.
  • the complement inhibitor may be administered orally.
  • the cachexia may be cancer cachexia.
  • the cachexia may be a non-cancer cachexia associated with a disorder selected from the group consisting of HIV/AIDS, end-stage renal failure, chronic obstructive pulmonary disease (COPD), and geriatric cachexia.
  • COPD chronic obstructive pulmonary disease
  • An aspect of the invention provides a method for diagnosing cachexia in a subject in need thereof, the method comprising: obtaining a saliva sample from the subject; stabilizing the saliva sample; determining a level of TNFa present in the pretreated saliva sample; comparing the determined value of the TNFa with that of a control value of TNFa derived from a saliva sample of an unaffected control group sample; and displaying the comparison of the determined value and the control value, wherein the determined value being greater than the control value is indicative of cachexia in the subject.
  • the determined value being at least 1.5 times greater than the control value may be indicative of cachexia in the subject.
  • the cachexia may be cancer cachexia.
  • the cachexia may be a non-cancer cachexia associated with a disorder selected from the group consisting of HIV/AIDS, end-stage renal failure, chronic obstructive pulmonary disease (COPD), and geriatric cachexia.
  • the control value of TNFa may range from 150 pg/ml to 175 pg/ml.
  • Figure 1 is a Western blot showing the effect of APAC on TNFa stimulation of C3 expression in the human breast cancer cell line BT 474.
  • Lanes 1-3 are 3 independent experiments using 3 untreated batches of BT474 cells.
  • Lanes 3-6 are the same batches after treatment for 24 hours with 1 ng/ml TNFa.
  • C3 production is substantially upregulated by the TNFa.
  • Lanes 7-9 are the same batches treated in the same way but with the addition of 30 ⁇ APAC .
  • the upregulated C3 production is blocked indicating that APAC is an inhibitor of TNFa stimulation of C3 production in the BT 474 breast cancer cell line.
  • FIG. 2 is a Western blot showing the effect of APAC on TNFa stimulation of C3 and C9 expression in the human pancreatic cell line BxPC3.
  • Lanes 1-3 are 3 independent experiments using 3 untreated batches of BxPC3 cells.
  • Lanes 3-6 are the same batches after treatment for 24 hours with 1 ng/ml TNFa.
  • C3 and C9 production is substantially upregulated by the TNFa.
  • Lanes 7-9 are the same batches treated in the same way but with the addition of 30 ⁇ APAC .
  • the upregulated C3 and C9 production is blocked indicating that APAC is an inhibitor of TNFa stimulated production of C3 and C9 in the human pancreatic cancer cell line.
  • FIG. 3 is a Western blot showing the effect of APAC on TNFa stimulation of C3 and C9 expression in the human colon cancer cell line LS180.
  • Lanes 1-3 are 3 independent experiments using 3 untreated batches of LS180 cells.
  • Lanes 3-6 are the same batches after treatment for 24 hours with 1 ng/ml TNFa.
  • C3 and C9 production is substantially upregulated by the TNFa.
  • Lanes 7-9 are the same batches treated in the same way but with the addition of 30 ⁇ APAC .
  • the upregulated C3 and C9 production is blocked indicating that APAC is an inhibitor of TNFa stimulated production of C3 and C9 in the human LS180 colon cancer cell line.
  • Figure 4 is a Western blot showing the effect of APAC on TNFa stimulation of C3 and C9 expression in human microglia.
  • Lanes 1-3 are 3 independent experiments using 3 untreated batches of human microglia.
  • Lanes 3-6 are the same batches after treatment for 24 hours with 1 ng/ml TNFa.
  • C3 and C9 production are upregulated by the TNFa.
  • Lanes 7-9 are the same batches treated in the same way but with the addition of 30 ⁇ APAC. The upregulated C3 and C9 production is blocked indicating that APAC is an inhibitor of TNFa stimulated production of C3 and C9 in the human microglia.
  • FIG. 5 is a Western blot showing the effect of APAC on TNFa stimulation of C3 and C9 expression in human astrocytes.
  • Lanes 1-3 are 3 independent experiments using 3 untreated batches of human microglia.
  • Lanes 3-6 are the same batches after treatment for 24 hours with 1 ng/ml TNFa.
  • C3 and C9 production are not upregulated by the TNFa.
  • Lanes 7-9 are the same batches treated in the same way but with the addition of 30 ⁇ APAC. Again there is no effect. These data indicate that TNFa does not stimulate production of C3 and C9 in human astrocytes.
  • Figure 6 is a graph plotting an ELISA kit readout of TNFa in the concentration range from zero to 1000 pg/ml. These data demonstrate a linear relationship between absorbance values at 450 nm and TNFa in pg/ml in the range of zero to 1 ,000 pg/ml.
  • FIG. 7 is a photograph showing immunohistochemical detection of TNFa in the cerebral cortex of a patient who died from pancreatic cancer. TNFa was
  • FIG. 8 is a photograph showing immunohistochemical detection of TNFa in the cerebral cortex of a patient who died from a sudden heart attack. TNFa was
  • Figure 9 is a graph plotting binding of APAC to a TNFa peptide as a function of the peptide concentration. Binding of APAC is linear in the range of 0-5 nmol/ml of APAC and 0-175 nmol/ml of TNFa peptide.
  • Figure 10 is a graph plotting binding of DAS to a TNFa peptide as a function of the peptide concentration. Binding of DAS is linear in the range of 0-5 nmol/ml of DAS and 0-175 nmol/ml of TNFa peptide.
  • Figure 1 1 is a graph plotting salivary TNFa levels over time of a patient suffering from terminal leukemia. Treatment with APAC reversed elevated salivary TNFa.
  • Figure 12 is a graph plotting salivary TNFa levels over time of a patient suffering from terminal breast cancer. Treatment with APAC reversed elevated salivary TNFa.
  • Figure 13 is a graph plotting salivary TNFa levels over time of a patient suffering from terminal ovarian cancer. Treatment with APAC reversed elevated salivary TNFa.
  • Figure 14 is a graph plotting salivary TNFa levels over time of a patient suffering from terminal colon cancer. Treatment with DAS reversed elevated salivary TNFa.
  • APAC aurin polycarboxylic acid complex
  • APAC aurin polycarboxylic acid complex
  • the low molecular weight components include aurin tri-, quadra-, penta- and hexacarboxylic acids.
  • Methods for obtaining APAC also known as the aurin tricarboxylic acid complex (ATAC) are described in US patent publication no. US2015/0065573 and Lee et al. (2012), incorporated by reference herein in their entirety.
  • cancer refers to the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • cancer includes cancer of any origin, including benign and malignant cancers, metastatic and non-metastatic cancers, and primary and secondary cancers.
  • cancer includes reference to cancer cells.
  • cancers include, but are not limited to, cancers of the bladder, blood, bone, brain/CNS, breast, cervix, colon, duodenum, esophagus, eye, gall bladder, heart, kidney, larynx, liver, lung, mouth, ovary, pancreas, pharynx, prostate, rectum, stomach, testis, uterus, as well as AIDS-related cancers, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, melanoma, leukemia (including lymphocytic leukemia, hairy cell leukemia, and acute myelogenous leukemia), choriocarcinoma, rhabdomyosarcoma, and neuroblastoma.
  • AIDS-related cancers Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, melanoma
  • leukemia including lymphocytic le
  • an "effective amount” as used herein refers to the amount of the active agent sufficient to elicit a desired biological response (or, equivalently, to inhibit an undesired biological response).
  • the absolute amount of a particular agent that is effective may vary depending on such factors as the desired biological endpoint, the agent to be delivered, the target tissue, etc.
  • an "effective amount” may be administered in a single dose, or may be achieved by administration of multiple doses.
  • prodrug refers an agent that is converted into the parent drug in vivo.
  • a prodrug upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound.
  • a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.
  • problems associated with the compound such as solubility, absorption and distribution, site specificity, instability, prolonged release, toxicity, poor patient acceptability, and formulation.
  • a common prodrug form for drugs containing alcohol or carboxylic acid functional groups is an ester. Methods of making prodrugs are well known (e.g. Balant (1990); Bundgaard (1991); Silverman (1992)).
  • the term “treat”, “treating” and “treatment” as used herein refers to relief, reduction or alleviation of at least one symptom of a disease or condition in a subject.
  • treatment can be diminishment of one or several symptoms of a disease or condition or complete eradication of a disease or condition.
  • Cancers may be relatively benign until yet to be identified factors induce TNFa production leading to cachexia.
  • TNFa stimulation also induces cells to upregulate production of complement.
  • Such upregulation might cause them to generate and release vascular endothelial growth factor (VEGF).
  • VEGF vascular endothelial growth factor
  • Complement upregulation may also provide enhanced protection of cancer cells by expressing elevated levels of such self-protective proteins as factor H, protectin (CD 59), decay accelerating factor, and possibly others.
  • aspects relate to methods of treating cachexia by administration to a human subject of an effective amount of a dimer of acetyl salicylic acid, aurin tricarboxylic acid
  • APAC aurin polycarboxylic acid complex
  • the administration route of the active agent, prodrugs thereof, or salts thereof, alone or in a composition in terms of effect may be local or systemic (enteral or parenteral), and in terms of location may for example be buccal, epicutaneous, epidural, intraarticular, intracardiac, intracavernous, intracerebral, intracerebroventricular, intradermal, intramuscular, intraosseous, intraperitoneal, intrathecal, intrauterine, intravaginal, intravenous, intravesical, intravitreal, nasal, oral, rectal, subcutaneous, sublingual, sublabial, transdermal, transmucosal, and the like.
  • oral administration may be in the form of capsules, cachets, pills, tablets, lozenges, pastes, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles or as mouth washes and the like.
  • compositions in solid dosage forms for oral administration include capsules, tablets, pills, dragees, powders, granules and the like.
  • the solid dosage forms may be scored or prepared with coatings and shells, such as enteric coatings and other coatings.
  • compositions in liquid dosage forms for oral administration include emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • topical or transdermal administration may be in the form of powders, sprays, ointments, pastes, creams, lotions, gels, solutions, controlled-release patches and inhalants.
  • parenteral administration e.g. intravenous administration
  • oral administration may be in the form of a prodrug of the active agent.
  • the cell types were exposed to TNFa stimulation in vitro.
  • the cell types could be various cancer cell lines or non-malignant cells, such as microglia and astrocytes.
  • Figure 1 is a Western blot illustrating the effect of TNFa on C3 expression in the human breast cancer cell line BT474.
  • the cell line does not express C9.
  • TNFa induced a substantial increase in C3 production which was blocked by APAC.
  • FIG. 2 is a Western blot illustrating the effect of TNFa on C3 and C9 expression in the human pancreatic cancer cell line BxPC-3. At 1 ng/ml, TNFa similarly induced a substantial increase in C3 and C9 production which was also blocked by APAC.
  • Figure 3 is a Western blot of the colon cancer cell line LS180, showing a comparable effect on C3 and C9 for this malignant cell line which was also blocked by APAC.
  • TNFa is also generated by normal tissue.
  • Figure 4 is a western blot showing the production of TNF by human microglia, while Figure 5 shows a lack of production by human astrocytes.
  • Endogenous TNFa production can be measured by ELISA.
  • the data reported herein used the Peprotech human TNFa kit (catalog 900-T25) following directions of the manufacturer. Alternative ELISA methods, not relying on commercial manufacturers, could be employed.
  • Figure 6 is a graph demonstrating a linear relationship between absorbance (at 450 nm) and added TNFa in the concentration range from zero to 1000 pg/ml. This standard curve was used to calculate TNFa production in various organs and in saliva as presented herein.
  • Table 1 shows that TNFa is produced by every tissue of the body that was measured. The values range from 21 pg/ml in the heart to 122 pg/ml in the kidney. Salivary TNFa levels can be taken as a surrogate for submandibular gland production of TNFa. Salivary TNFa levels in healthy volunteers shown in Table 2 demonstrate that this level is remarkably constant regardless of age, and ranges from 155-175 pg/ml. TNFa is substantially elevated in terminal cancer patients typically ranging from 405-462 pg/ml.
  • a method for diagnosing cachexia comprises:
  • the stabilization step may involve known methods for stabilizing TNFa, such as those described by Lee et al. (2017), incorporated herein by reference.
  • the detection step is designed to treat the stabilized saliva sample with an TNFa antibody in such a way as to bind essentially all of the TNFa present in the sample.
  • the detection step may involve an immunoassay, such as an ELISA test based on an antigen-antibody reaction using TNFa as the antigen to be measured.
  • the capture antibody may be a polyclonal antibody specific for TNFa.
  • the bound TNFa is then detected by a second TNFa antibody which does not cross react with the first TNFa antibody.
  • the second TNFa antibody may be a monoclonal antibody, such as a mouse monoclonal antibody.
  • Biotin may then be bound to the monoclonal antibody or to a third IgG antibody to which biotin is bound.
  • the biotin levels are detected by first treating with a streptavidin solution linked with horse radish peroxidase (HRP) followed by treatment with a tetramethylbenzidine solution to detect the HRP by reading the resulting color in a spectrophotometer.
  • An ELISA standard concentration graph of target TNFa may be obtained, for example, by absorbance detection, fluorescence detection, luminescence detection, or electrochemical detection.
  • Figure 6 shows a standard concentration graph for TNFa obtained by absorbance at 450 nm.
  • the immunoassay may be performed by a method capable of directly or indirectly detecting TNFa. Examples of such alternative methods include MS (Mass Spectrometry), MS/MS, and liquid chromatography.
  • the comparison step may involve comparing the detected level of TNFa obtained from the detection step against a predetermined level of TNFa.
  • the predetermined level of TNFa may be obtained from concurrent or previous saliva samples from normal individuals without AD and without any genetic predisposition for AD.
  • the displaying step involves displaying values, diagrams, illustrations, and the like.
  • This step is preferably a step that can assist in assessing the difference between the detected value and the predetermined value.
  • the difference may be displayed by the ratio of the detected value to the predetermined value.
  • a diagnosis of cachexia may be made, for example, if this ratio exceeds 1.5, or 2.0, or 2.5 or 3.0 or 3.5 or 4.0.
  • FIG. 7 shows TNFa immunohistochemical staining of the brain of a patient who died from pancreatic cancer using the MyBiosource rabbit polyclonal antibody (MBS7002356, 1 :1000 dilution). There is heavy immunostaining of capillaries.
  • Figure 8 shows comparable staining of the brain of a patient who died from a sudden heart attack. There is only faint background staining. Detailed methodology is described in Schwab et al (2013), incorporated by reference herein.
  • a method for preparing dimers of acetyl salicylic acid is described in PCT publication no. WO 2015/070354 and Lee et al. (2015), incorporated by reference herein.
  • An exemplary dimer of acetyl salicylic acid is 5,5'-methylenebis-2-acetoxybenzoic acid (DAS) and its isomers, 2-acetoxy-3-(4-acetoxy-3-carboxybenzyl)benzoic acid,
  • TNFa TNFa peptide spot array was synthesized on a cellulose membrane using a Semi-automated AutoSpot robot (INTAVIS, USA) covering the 233 amino acid sequence of TNFa. A total of 1 12 peptides, each shifted by 2 amino acids were synthesized. The TNFa membrane was soaked in 50% methanol in 10mM PBS (pH7.4) for 2 minutes, then washed twice with PBS.
  • the membrane was then incubated with 1 mM of APAC or DAS in PBS (10 mM, pH7.4) for one hour at 37°C. After washing 3 times with PBS, positive images were captured with a SYPRO Ruby filter for APAC and an Alexa 680 filter for DAS by the Chemidoc MP imaging System (Bio-Rad, USA).
  • TNFa-A2 peptide A strongly positive peptide sequence was chosen for synthesis of a potential inhibitor of TNFa binding.
  • the sequence of this TNFa-A2 peptide was
  • the invention can be further understood by reference to the following examples, which are provided by way of illustration and are not meant to be limiting.
  • the examples are of human cancer cases that had become cachexic.
  • the patients had salivary TNFa levels ranging from 405 to 462 pg/ml.
  • the TNFa in these cases was restored to normal levels by treatment with DAS (4,4'-diacetoxy-1 , 1 biphenyl-3,3' dicarboxylic acid) or APAC for 10-21 days.
  • the inventors have determined that cancer patients who have deteriorated into a cachexic state have a sharp increase in their salivary levels of TNFa. This increase is rapidly reduced to normal levels by oral intake of complement inhibitors such as APAC and DAS.
  • Example 1 Salivary TNFa restoration to normal with APAC treatment
  • the patient was a 60 year old male diagnosed with terminal leukemia and cachexia. He was given a life expectancy of one month. Two weeks later the inventors obtained a saliva sample (Day 1) at the time of his biweekly blood transfusion.
  • the TNFa level was found to be 454 pg/ml instead of the expected normal level of about 160 pg/ml.
  • On Day 1 he began oral intake of 300 mg/3X/day of APAC.
  • By Day 7 he no longer needed any blood transfusions, and his appetite and well-being improved.
  • a second saliva sample was taken on Day 10 and the TNFa level had dropped to 349 pg/ml.
  • a further sample was taken on Day 15 and the TNFa level was reduced to 205 pg/ml.
  • the patient was a 54 year old woman diagnosed with stage IV ductal breast carcinoma. She underwent a double mastectomy, chemotherapy and radiation therapy but the side effects from her treatments were so severe that she had bone pain, was unable to walk and was exhausted all the time. Her cancer continued to progress, she became cachexic, and her salivary TNFa was measured at 295 pg/ml. At this point she started taking APAC (3X300mg/day). After 10 days on APAC (3X100 mg/day) her TNFa values had returned to normal at 160 pg/ml and symptoms of cachexia subsided (for example, her bone pain disappeared, and her strength restored to the point where she was able to travel overseas). The data are shown in Figure 12.
  • the patient was a 57 year old woman diagnosed with ovarian cancer and cachexia. She was recently treated with Re-Stimulated Autologous Tumor-Infiltrating Lymphocytes (TILS) followed by low-dose interleukin-2. The treatment was unsuccessful and it was anticipated that the subsequent scans would show metastatic tumor growth. She was on no treatment except for pain medications (17.5 mg methadone and 80 mg OxyNeo). That was also unsuccessful.
  • Her TNFa saliva level was 394 pg/ml before she started taking APAC (100mg/3X/day). Her salivary TNFa level returned to normal sometime between 18 and 25 days and symptoms of cachexia subsided. The data are shown in Figure 13.
  • the patient was a 66 year old woman diagnosed with stage IV peritoneal carcinomatosis and cachexia.
  • a saliva sample was obtained at this time and she was found to have an elevated TNFa level of 394 pg/ml (Day 0).
  • a second sample was taken 3 days later and was found to have increased to 406 pg/ml.
  • She was then started on DAS (3X100 mg/day).
  • Five days into her treatment (Day 8) her TNFa level had dropped to 288 pg/ml.
  • her TNFa had returned to a normal level of 161 pg/ml and symptoms of cachexia subsided.
  • the data are shown in Figure 13.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Biomedical Technology (AREA)
  • Urology & Nephrology (AREA)
  • Cell Biology (AREA)
  • Biochemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Food Science & Technology (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention porte sur une méthode de traitement de la cachexie. La méthode comprend l'administration à un être humain en ayant besoin d'une quantité efficace d'un inhibiteur du complément. L'inhibiteur du complément peut être un dimère d'acide acétyl salicylique, y compris l'acide 5,5'-méthylènebis(acide 2-hydroxybenzoïque), 4,4'-diacétoxy-1,1 biphényl-3,3' dicarboxylique ou un sel pharmaceutiquement acceptable de celui-ci. L'inhibiteur du complément peut être de l'acide aurine tricarboxylique, de l'acide aurine quadracarboxylique, de l'acide aurine pentacarboxylique, de l'acide aurine hexacarboxylique, des combinaisons de ceux-ci, et des sels pharmaceutiquement acceptables de ceux-ci. L'inhibiteur du complément peut être un promédicament ester des composés précédents.
PCT/CA2018/050639 2017-05-31 2018-05-30 Méthodes de diagnostic et de traitement de la cachexie Ceased WO2018218357A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP18810657.9A EP3630121A4 (fr) 2017-05-31 2018-05-30 Méthodes de diagnostic et de traitement de la cachexie
CA3059278A CA3059278A1 (fr) 2017-05-31 2018-05-30 Methodes de diagnostic et de traitement de la cachexie
JP2019558441A JP2020521723A (ja) 2017-05-31 2018-05-30 悪液質の診断方法および治療方法
US16/605,785 US20200121697A1 (en) 2017-05-31 2018-05-30 Methods for diagnosing and treating cachexia

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201762513277P 2017-05-31 2017-05-31
US62/513,277 2017-05-31

Publications (1)

Publication Number Publication Date
WO2018218357A1 true WO2018218357A1 (fr) 2018-12-06

Family

ID=64454118

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CA2018/050639 Ceased WO2018218357A1 (fr) 2017-05-31 2018-05-30 Méthodes de diagnostic et de traitement de la cachexie

Country Status (5)

Country Link
US (1) US20200121697A1 (fr)
EP (1) EP3630121A4 (fr)
JP (1) JP2020521723A (fr)
CA (1) CA3059278A1 (fr)
WO (1) WO2018218357A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006012373A2 (fr) * 2004-07-20 2006-02-02 Critical Therapeutics, Inc. Polytherapies hmgb
WO2011107591A1 (fr) * 2010-03-05 2011-09-09 Rigshospitalet Molécules chimériques inhibitrices d'activation du complément
CA2878734A1 (fr) * 2012-07-13 2014-01-16 Aurin Biotech Inc. Inhibition selective du complexe d'attaque membranaire du complement et de la c3 convertase par des composants a faible poids moleculaire du complexe synthetique d'acide pararosol ique tricarboxylique
CA2930459A1 (fr) * 2013-11-18 2015-05-21 Aurin Biotech Inc. Dimeres de l'acide acetylsalicylique, leur synthese, et leurs utilisations pour prevenir et traiter des troubles medies par le complement

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5700466A (en) * 1981-09-08 1997-12-23 The Rockefeller University Method of ameliorating or preventing septic shock using a monoclonal antibody specific to cachectin/tumor necrosis factor

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006012373A2 (fr) * 2004-07-20 2006-02-02 Critical Therapeutics, Inc. Polytherapies hmgb
WO2011107591A1 (fr) * 2010-03-05 2011-09-09 Rigshospitalet Molécules chimériques inhibitrices d'activation du complément
CA2878734A1 (fr) * 2012-07-13 2014-01-16 Aurin Biotech Inc. Inhibition selective du complexe d'attaque membranaire du complement et de la c3 convertase par des composants a faible poids moleculaire du complexe synthetique d'acide pararosol ique tricarboxylique
CA2930459A1 (fr) * 2013-11-18 2015-05-21 Aurin Biotech Inc. Dimeres de l'acide acetylsalicylique, leur synthese, et leurs utilisations pour prevenir et traiter des troubles medies par le complement

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BALKWILL, F: "Tumour Necrosis Factor and Cancer", NATURE REVIEWS CANCER, vol. 9, no. 5, May 2009 (2009-05-01), pages 361 - 375, XP055554306 *
BEUTLER, B ET AL.: "Identity of tumour necrosis factor and the macrophage-secreted factor cachectin", NATURE, vol. 316, 8 August 1985 (1985-08-08), pages 552 - 554, XP002945319 *
MCGEER, PL ET AL.: "A review of human diseases caused or exacerbated by aberrant complement activation", NEUROBIOLOGY OF AGING, vol. 52, 1 April 2017 (2017-04-01), pages 12 - 22, XP055554310 *
See also references of EP3630121A4 *

Also Published As

Publication number Publication date
EP3630121A1 (fr) 2020-04-08
EP3630121A4 (fr) 2021-03-03
JP2020521723A (ja) 2020-07-27
US20200121697A1 (en) 2020-04-23
CA3059278A1 (fr) 2018-12-06

Similar Documents

Publication Publication Date Title
Kang et al. Forkhead box O3 plays a role in skeletal muscle atrophy through expression of E3 ubiquitin ligases MuRF-1 and atrogin-1 in Cushing’s syndrome
Chen et al. Ghrelin prevents tumour‐and cisplatin‐induced muscle wasting: characterization of multiple mechanisms involved
Tam et al. Peripheral cannabinoid-1 receptor blockade restores hypothalamic leptin signaling
Mantovani et al. Cancer cachexia: medical management
US8552050B2 (en) Activators of pyruvate kinase M2 and methods of treating disease
Song et al. Epsins 1 and 2 promote NEMO linear ubiquitination via LUBAC to drive breast cancer development
Lin et al. Targeting positive feedback between BASP1 and EGFR as a therapeutic strategy for lung cancer progression
Jaszberenyi et al. Suppression of the proliferation of human U-87 MG glioblastoma cells by new antagonists of growth hormone-releasing hormone in vivo and in vitro
Yin Pericyte-derived heme-binding protein 1 promotes angiogenesis and improves erectile function in diabetic mice
EP4324841A1 (fr) Peptide de pénétration cellulaire, peptide anti-cancéreux, et composition pharmaceutique pour prévenir ou traiter le cancer le comprenant
US20230226044A1 (en) Oxopiperazine derivatives for the treatment of cancer
Blishchenko et al. Antitumor effect of valorphin in vitro and in vivo: combined action with cytostatic drugs
US20200121697A1 (en) Methods for diagnosing and treating cachexia
CN119770656A (zh) 一种治疗靶点在制备抗癌细胞顺铂耐药性药物上的应用
CN115942970A (zh) N-酰基氨基酸产物及用途
Peng et al. GALNT9 enrichment attenuates MPP+-induced cytotoxicity by ameliorating protein aggregations containing α-synuclein and mitochondrial dysfunction
JP2022535086A (ja) 修飾ペプチドおよび関連する使用方法
US7838495B2 (en) Compositions and methods of use of EPB1, and ErbB3 binding protein
US20230133141A1 (en) Methods for treating multidrug resistant breast cancer
CN115427062A (zh) 用于脂肪肝病的修饰的吻素受体激动剂
US10369191B2 (en) Modulation of epigenetic stress response
Gates The Incretin Mimetic Drug Tirzepatide Attenuates Mammary Tumor Growth Independently of Insulin-Like Growth Factor-1 Signaling
KR20200067785A (ko) 세포에서의 자가포식작용 억제용 조성물, 및 이를 포함하는 종양성 질환의 예방 또는 치료용, 또는 항암제 내성 억제용 약학적 조성물
KR20090042105A (ko) Ｓｉｒｔ１활성조절용 조성물
US11137400B2 (en) Methods for predicting and determining responsiveness to activators of JNK kinase

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18810657

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 3059278

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2019558441

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2018810657

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2018810657

Country of ref document: EP

Effective date: 20200102